JPH02289A - Optically active amine-boron-based compound, asymmetric reducing agent containing the same compound as active ingredient and production of optically active compound using the same agent - Google Patents

Abstract

NEW MATERIAL:A compound obtained from an optically active amine derivative expressed by the formula (R<1> is H, lower alkyl or lower alkoxy; R<2> is lower alkyl: * indicates asymmetric carbon; OH is substituted at the o- or m- position of a substituent group having the asymmetric carbon) and a boron hydride compound. USE:An asymmetric reducing agent. PREPARATION:A boranedimethyl sulfide complex is added to a solution consisting of (+)-1-(2-hydroxyphenyl)ethylamine and deuterated chloroform at 0 deg.C and the resultant mixture is stirred. The boranedimethyl sulfide is further added thereto and the mixture is stirred. Thereby, an optically active amine- boron-based compound is obtained.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention relates to an optically active amine-boron compound, and more specifically, the present invention relates to an optically active amine-boron compound, and more specifically, the present invention relates to an optically active amine-boron compound, and more specifically, the present invention relates to an optically active amine-boron compound, Optically active amines represented by the general formula (V) (in which R6 and R'l have the same meanings as above, and the umbrella represents an asymmetric carbon) 1. A method for producing an optically active compound, the method comprising producing an optically active compound.

(In the formula, R1 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group, R2 represents a lower alkyl group, * means an asymmetric carbon, and OH5 represents a substituent having an asymmetric carbon.
or m-position. ) and an optically active amine obtained from a borohydride compound.
This relates to boron compounds.

<Prior Art> Until now, α-phenethylamine-boron compounds have been known as amine-boron compounds with optically active benzylamine derivatives as ligands, and these compounds have been used as asymmetric reducing agents. It is also known that R
ichard F, Boreh and Stephen
R, Levitan; J, Org, Chem, +37
．． No. 14.2347 (1972)).

<iIu to be Solved by the Invention> However, there is no known amine-boron compound using as a ligand an optically active benzylamine derivative represented by the general formula (1) in which a hydroxy group is replaced with a phenyl group. .

Furthermore, when an amine-boron compound with optically active α-phenethylamine as a ligand is used as an asymmetric reducing agent, the optical yield of the optically active compound as a product is low, or the coordination with the reduction product is low. There were problems such as it was not easy to separate children from their children.

<Means for Solving the Problems> The present inventors have synthesized various amine-boron compounds using hensylamine derivatives as ligands, and as a result of repeated research, it has been found that the hydroxy group is at the 0-position or the m-position of the phenyl group. Amine hepta-boron compounds with an optically active benzylamine derivative substituted at a specific position, ie, as a ligand, are extremely useful as asymmetric reducing agents, and give reduction products with extremely high optical yields, and also coordinate They found that separation and recovery of the offspring was extremely easy, and after further various studies, they completed the present invention.

That is, the present invention relates to the general formula (1) (wherein R' represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group, Rz represents a lower alkyl group, * means an asymmetric carbon, and the OH group represents an asymmetric An optically active amine-boron compound obtained from an optically active amine derivative represented by The present invention provides a reducing agent and a method for producing an optically active compound using the reducing agent.

The optically active amine-boron compound of the present invention has as a ligand a specific optically active benzylamine derivative (1) in which a hydroxy group is substituted at the 0-position or the m-position of a phenyl group. Examples of the substituent R1 of the benzylamine derivative include hydrogen, methyl, ethyl, n-propyl, 1so-7"lopyl, n-butyl, 1so-butyl, 5ec-butyl, -butyl, n-pentyl, n-
Lower alkyl groups such as hexyl, methoxy, ethoxy, n
-propoxy, 1so-propoxy, n-butoxy, 1
Examples include lower alkoxy groups such as so-butoxy, 5ec-butoxy, n-pentyloxy, and n-hexyloxy.

Furthermore, examples of Rg include lower alkyl groups similar to R1. Most preferably, the OH group is substituted at the 0-position with respect to the substituent having an asymmetric carbon.

Specific compounds include, for example, optically active 1-(2-hydroxy-3-ethylphenyl)ethylamine, 1-(2-ethylphenyl)ethylamine,
-hydroxy-3-methylphenyl)ethylamine, 1
-(2-hydroxy-3-methoxyphenyl)ethylamine, 1-(2-hydroxy-3-ethoxyphenyl)
Ethylamine, 1-(2-hydroxy-5-methoxyphenyl)ethylamine, 1-(2-hydroxyphenyl)ethylamine, 1-(2-hydroxy-5-ethoxyphenyl)ethylamine, 1-(2-hydroxyphenyl)propylamine , 1-(3-hydroxyphenyl)
Ethylamine, 1-(2-hydroxy-3-ethylphenyl)propylamine, 1-(2-hydroxy-3-methylphenyl)propylamine, 1-(2-hydroxy-3-methylphenyl)propylamine, 1-( 2-Hydroxy-3-ethylphenyl)propylamine, 1-
(2-hydroxy-3-methoxyphenyl)propylamine, 1-(2-hydroxy-3-ethoxyphenyl)propylamine, 1-(2-hydroxy-5-monomethylphenyl)ethylamine, 1-(2-hydroxy- 5
-ethylphenyl)ethylamine, 1-(2-hydroxy-5-methoxyphenyl)propylamine, 1-(2
-Hydroxy-5-ethoxyphenyl)propylamine, 1-(2-hydroxy-4-methylphenyl)ethylamine, 1-(2-hydroxy-4-methoxyphenyl)ethylamine, 1-(2-hydroxy-4-methylphenyl) ) propylamine, 1-(2-hydroxy-4
-methoxyphenyl)propylamine, 1-(3-hydroxyphenyl)propylamine, 1-(2hydroxy-6-methylphenyl)ethylamine, 1-(2-hydroxy-6-ethoxyphenyl)ethylamine, 1-(
Examples include 2-hydroxy-6-methylphenyl)propylamine, 1-(2-hydroxy-6-ethoxyphenyl), and propylamine.

Further, such optically active benzylamine derivative (1) can be produced, for example, by the following route.

More specifically, for example, Williamaison 5ynthe of (■) ketone compound and benzyl halide
The benzyl compound of (■) is obtained by sis, and this is reacted with hydroxyamine or alkoxyamines in a solvent such as pyridine to form the oxime compound of (IX), which is then subjected to asymmetric reduction to form the optical compound of (X). Active amines can be produced. Here, the asymmetric reduction is J, Chem, S
oc,, PERIIN TRANS, I, 1985.2
The method of 039 etc. can be referred to, and the compound (■) can also be used as the asymmetric ligand.

Optically active amines (X) can be obtained by catalytic hydrogenation of the oxime compound (IX) using a hydrogenation catalyst such as palladium, platinum, or Raney nickel, or by catalytic hydrogenation of lithium aluminum hydride, sodium borohydride, borane-tetrahydrofuran complex, borane-dimethyl It can also be obtained by reducing the racemic amines (X) with a metal hydride such as a sulfide complex, and then optically resolving this.

Next, by subjecting the optically active amine (X) to hydrogenolysis, the optically active benzylamine derivative (+) can be produced.

Hydrogenolysis can be carried out by a commonly used method, and is carried out, for example, in the presence of a catalyst such as palladium, platinum, or Raney nickel. Also, optically active amines (X)
can also be used in the form of salts with mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and propionic acid.

The solvent is not particularly limited as long as it does not poison the catalyst, but alcohols such as methanol, ethanol, isopropanol, or a mixed solvent of these and water are usually used. Further, when using a catalyst other than Raney nickel, the reaction can be carried out in the presence of mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and propionic acid.

The reaction is usually carried out at -50 to 60°C and at a rate of 10 to 150 kg/c, but the reaction proceeds satisfactorily even at room temperature and normal pressure.

Next, a method for producing an amine-boron compound of the present invention using the optically active benzylamine derivative of (1) as a ligand and a method for producing an optically active compound using the same will be explained.

The amine-boron compound of the present invention is, for example, a derivative (1
) and hydrogenated boron compounds such as diborane, borane tetrahydrofuran complex, and borane dimethyl sulfide complex. The molar ratio of the borohydride compound to the derivative (1) is usually 1 to 5 moles, preferably 2 to 3 moles, in terms of boron.

The solvent is not particularly limited as long as it does not participate in the reaction, but examples include ethers or thioethers such as diethyl ether, tetrahydrofuran, diglyme, and dimethyl sulfide, aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, and methylene chloride. , 1,2-dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, or mixed solvents thereof.

The preparation temperature is usually -78 to 100°C, preferably -4
The temperature is 0 to 50°C, and it is usually prepared under an inert gas atmosphere such as nitrogen or argon.

In this way, the amine-boron compound of the present invention using the derivative (1) as a ligand is produced, and this compound is extremely useful as an asymmetric reducing agent, and is capable of reacting with, for example, asymmetric ketone oximes and asymmetric ketones. As a result, optically active amines can be obtained from the former and optically active alcohols can be obtained from the latter with high optical yields, and the separation of the ligand and reduction product can be done using PH1Fl and a simple operation of liquid separation. It becomes possible.

First, to explain the case of asymmetric reduction of asymmetric ketone oximes, for example, from the anti-isomer, syn-isomer, or a mixture of either of these oximes of the general formula (11), the general formula (TV) is reduced. The optically active amines shown can be produced.

(In the formula, R3 represents a hydrogen atom, an alkyl group, an aralkyl group, or an alkyl-substituted silyl group, R', R'
(represents a lower alkyl group, aryl group, or aralkyl group, and are not the same, * represents an asymmetric carbon) Here, as the substituent R3 in oxime M (II), for example, methyl, ethyl, propyl , butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, cyclooctyl, nonyl, decyl, etc., alkyl having 1 to 10 carbon atoms, benzyl, β
Examples include aralkyl groups having 7 to 11 carbon atoms such as phenethyl and naphthylmethyl, and alkylsilyl groups having 3 to 12 carbon atoms such as trimethylsilyl, dimethyl-t-butylsilyl, tri-n-propylsilyl, and tri-n-butylcidyl.

Further, as substituents R' and R', phenyl, 2-3-
14-pyridyl, o-, m-, p-chlorophenyl, o
−.

Wei-1p-bromphenyl, 2.3-12,4-12,
Halogen-substituted phenyl such as 5-12,6 dichlorophenyl, 0-+ ff1-+P-methylphenyl, o-,
m-, p-ethylphenyl, O-+ m-++'-butylphenyl, 2.3-22I4-12.5-12,6-
Phenyl substituted with alkyl having 1 to 6 carbon atoms such as scintyl phenyl % O-+ I'l-+p-methoxyphenyl, O-+ m-, p-ethoxyphenyl, 011
1-+ Phenyl substituted with alkoxy having 2 to 6 carbon atoms such as p-propoxyphenyl, O-+ m-+p-benzyloxyphenyl, 2-jinzyloxy-3-methylphenyl, 2-benzyloxy-4-methylphenyl , 2-benzyloxy-5-methylphenyl, 2-benzyloxy-5-t-butylphenyl, 2-benzyloxy-3-methoxyphenyl, 2-benzyloxy-4
-Methoxyphenyl, 2-benzyloxy-5-methoxyphenyl, benzyloxy-substituted phenyl such as 2-benzyloxy-35-dichlorophenyl, aryl group with a total carbon number of 5 to 17 such as α-β-naphthyl, methyl , ethyl, propyl, butyl, pentyl, cyclopentyl,
Lower alkyl groups having 1 to 6 carbon atoms such as hexyl and cyclohexyl, benzyl, O-1-, p-tolylmethylnyl)methyl, (2,3-12,4-12,5-12,
6-syntylphenyl)methyl, 2-phenylethyl,
2-(o-.

p-tolyl)ethyl, (2,3-12,4-12,
Examples include aralkyl groups having 7 to 11 carbon atoms such as 5-52,6-syntylphenyl)ethyl and 3-phenylpropylnaphthylmethyl.

Typical ketone oximes include, for example, acetophenone, propiophenone, butyrophenone, isobutyrophenone, 2-acetylpyridine, 0-methoxyacetophenone, 〇-ethoxyacetophenone, 0-propoxyacetophenone, 0-benzyloxyacetophenone, α-acetonaphthone. , β-acetonaphthone, phenylbenzyl ketone, phenyl (p-tolylmethyl) ketone, phenyl (tolylmethyl ketone), phenyl (0-
tolyl methyl ketone), phenyl (2-phenylethyl) ketone, 2-butanone, 2-pentanone, 2-hexanone, 3-hexanone, 2-heptanone, 2-octanone, 3-heptanone, 3-octanone, cyclohexylmethyl ketone, Cyclohexyl ethyl ketone, cyclohexyl benzyl ketone, α-phenylacetone, (2-
Examples include oximes such as O-methyl, O-octyl, 0-cyclohexyl, O-benzyl, and 0-trinotylsilyl, such as phenylethyl) methyl ketone, (2-phenylethyl) ethyl ketone, and (3-phenylpropyl) methyl ketone. A mixture rich in either syn-isomer, anti-isomer, or syn-isomer or anti-isomer is used.

These ketone oximes can be easily produced from the corresponding ketones by known methods. In addition, when using either the syn isomer or the anti isomer, the remaining separated isomer is subjected to an isomerization reaction of syn isomer/anti isomer using a known method.
It can be converted back into the required isomer, allowing effective use of raw materials.

In the case of asymmetric reduction of asymmetric ketone oximes, the reducing agent is used at least 1 mole times, usually 1 to 6 times the amount of the ketone oxime, based on the di(1) tA, but 1 to 3 times the amount is sufficient. Able to achieve purpose.

The solvent for the reduction reaction is not particularly limited as long as it is an inert solvent that does not participate in the reduction reaction, but examples include aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, methylene chloride, 1,2-dichloroethane,
Halogenated hydrocarbons such as chloroform and carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran, dioxane and diglyme, and mixed solvents thereof are used. The amount used is usually 2 to 50 times the amount of ketone oximes.

Furthermore, the solvent used in the reducing agent preparation step may be used as it is as a solvent in the reduction step, or the above-mentioned solvent may be used in addition.

The reduction reaction is usually carried out under the same inert gas atmosphere as described above, and the reaction temperature is usually -30 to 100°C, industrially generally -10 to 50'C.

After the reduction reaction, the reducing agent is usually decomposed by adding an aqueous solution of a mineral acid such as hydrochloric acid to the reaction solution, and then the remaining organic layer is separated by making it alkaline with an alkaline aqueous solution such as an aqueous solution of caustic soda. Optically active amines, which are the desired reduction products, are recovered from. On the other hand, the aqueous layer is neutralized with a mineral acid such as hydrochloric acid or made acidic, and then the ligand is The optically active benzylamine derivative (1) is recovered in good yield without racemization.

This stuff can be reused.

Next, the case of asymmetric reduction of asymmetric ketones will be described. For example, optically active alcohols represented by the general formula (V) can be produced from ketones represented by the general formula (T[I).

(III) (V) (wherein R' and R' are lower alkyl groups, ary groups, aralkyl groups, or formula (Vl) (wherein, R may be substituted with halogen or haloalkyl group) (represents a phenyl group or cyclohexyl group) represents a 2-substituted-1-triazoleethylene group represented by (and cannot be the same, * represents an asymmetric carbon), where R', R' is, for example, the general formula (■).

Lower alkyl group similar to Ra and Rs in (TV),
71J- 2-substituted - having phenyl, chlorphenyl, bromphenyl, dichlorophenyl, dibromphenyl, trifluoromethylphenyl, trichloromethylphenyl, tribromomethylphenyl, cyclohexyl, etc. as the aralkyl group and the substituent R1 Examples include 1-triazoleethylene group.

Representative ketones include, for example, acetophenone, propiophenone, butyrophenone, isobutyrophenone, α-acetonaphthone, β-acetonaphthone, phenylbenzyl ketone, phenyl (p-tolylmethyl) ketone, phenyl (de-tolylmethyl) ketone, phenyl ( 〇-Todylmethyl)ketone, 2-butanone, 2-pentanone, 2-hexanone, 3-hexanone, 2-heptanone, 2-octanone, 1-phenyl-2-(1,2,4-
) riazol-1-yl)-4,4-dimethyl-1-penten-3-one, 1-(4-chlorophenyl)-2-
(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one, 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1
-yl)-4,4-dimethyl-1-penten-3-one, 1-cyclohexyl-2-(1,2,4-riazol-1-yl)-4,4-dimethyl-1-penten- 3-
on, 1-(4-)lifluoromethylphenyl)-2-(
1,2,4-)riazol-1-yl)-4,4-dimethyl-1-penten-3-one, 1-(3-bromophenyl)-2-(1,2゜4-triazol-1- )
-4,4-dimethyl-1-penten-3-one, 1-(
4-fluorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3
- Examples include on.

In the case of asymmetric reduction of ketones, the reducing agent is 0.5 times or more mole of the ketone in terms of derivative (1), usually 0.5 to
Although 6 moles are used, the purpose can be sufficiently achieved even with 1 to 3 moles.

The solvent for the reduction reaction is not particularly limited as long as it is an inert solvent that does not participate in the reduction reaction, but examples include aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene, methylene chloride, 1,2-dichloroethane,
Halogenated hydrocarbons such as chloroform and carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran, dioxane and diglyme, and mixed solvents thereof are used. Furthermore, the solvent used in the reducing agent preparation step may be used as it is as a solvent in the reduction step, or the above-mentioned solvent may be used in addition. The amount used is usually 2 to 50 times the amount of ketones.

The reduction reaction is usually carried out under the same inert gas atmosphere as described above, and the reaction temperature is usually -30 to 100°C, industrially generally -10 to 50°C.

After the reduction reaction, the reducing agent is usually decomposed by adding an aqueous solution of a mineral acid such as hydrochloric acid to the reaction solution, and optically active alcohols, which are the desired reduction products, are removed from the organic layer by separating the layers under acidic conditions. It will be collected. On the other hand, by neutralizing the aqueous layer with an alkaline aqueous solution such as ammonia, sodium bicarbonate, or sodium carbonate, and extracting with an organic solvent, the optically active benzylamine derivative (I), which is a ligand, can be produced in a high yield without racemization. It is well recovered. This stuff can be reused.

<Effects of the Invention> The optically active amine-boron compound of the present invention is extremely useful as an asymmetric reducing agent. For example, the optically active amine-boron compound of the present invention can be used to convert optically active amines from asymmetric oximes and optically active amines from asymmetric ketones. It has the advantage that active alcohols can be obtained in extremely high optical yields, and that the optically active benzylamine derivative, which is the ligand of the compound, can be separated and recovered very easily after reduction.

<Examples> Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto.

Reference example 1 (manufacturing example of benzyl compound) Ethanol 200 mff1 and metallic sodium 7.9 g
After preparing a sodium ethylate solution from (0.3435 g atoms), 2-hydroxyacetophenone 0.3
12 moles (42.52 g) and benzyl chloride 47.
47 g (0,375 mol) was added and stirred under reflux for 4 hours.

The filtrate was then cooled to room temperature to eliminate the generated salt, and the filtrate was concentrated under reduced pressure, extracted with toluene, washed with water, dried, and then distilled under reduced pressure to obtain 2-benzyloxyacetophenone 66.
．． 06 g was obtained.

2-hydroxypropiophenone, 2-hydroxy-3-methylacetophenone, 2-hydroxy-3-methoxyacetophenone, 2-hydroxy-5-methoxyacetophenone in place of 2-hydroxyacetophenone,
The corresponding benzyl compound was obtained using 3-hydroxyacetophenone.

Table 1 Enone 0.043 mol (9,77 g) and 0-methylhydroxyamine hydrochloride 4.35 g (0,0521 mol)
was added to 50ml of pyridine and heated at room temperature for 2 hours at 100°C.
The mixture was stirred for 1 hour. After cooling to room temperature, 300 d of water was added to separate the oil layer. Extract the aqueous layer with chloroform,
This and the oil layer were combined, washed with water, dried, and distilled under reduced pressure to obtain 10.77 g of 2-benzyloxyacetophenone-0-methyloxime.

Similarly, corresponding oxime compounds were obtained using the benzyl compounds obtained in Reference Examples 1-2 to 1-6.

The results are shown in Table 2.

Reference Example 2 (Production Example of Oxime Compound) A mixture of 13.79 g (0,054 mol) of 2-penzyloxyacetophyl obtained in Reference Example 1-1 was cooled to -78°C. After adding 4.31 g of borane dimethyl sulfide complex to this while stirring, the temperature was raised to room temperature over about 2 hours, and 4.31 g of borane dimethyl sulfide complex was further added and stirred for 15 minutes.

Next, 9.19 g of 2-benzyloxyacetophenone-0-methyloxime (0,
A mixture of 036 mol) and THFloWtl was added and stirred at room temperature for 20 hours, and then at 60''C for 1 hour.

Reference example 3 (optically active α-(benzyloxyphenyl)
-Production example of alkylamine) (3-1) (+)-1-(2-benzyloxyphenyl)ethylaminetetrahydrofuran (THF) 20 (ld and (S)-(
-)-2-Amino-3-methyl-1,1-diphenylpukuno Then, after adding 10 d of 10% hydrochloric acid,
．． Stirred for 5 hours. After reducing the pressure, the mixture was made alkaline by adding 10% aqueous sodium hydroxide solution and extracted twice with chloroform. After washing the organic layer with water, drying, and concentrating,
In order to remove and separate the ligand, the ligand, etc. was separated and removed by silica gel column chromatography using this as an elution solvent of ethyl acetate, and 6.08 g of (+)-1-(2-benzyloxyphenyl)ethylamine was obtained. Obtained.

'Hrv+r spectrum [δ,, @, CDCl5]
1.41 (3H, d), 2.16 (2H, S), 4.4
3 (IH, q).

5.08 (2H, S), 6.89-7.00 (21
1, steel).

7.12-7.23 (18, m), 7.28-7.44
(TO, m) The optical rotation of the hydrochloride of this product is [α) s”
+13.45° (C1.05, water).

This hydrochloride was recrystallized from isopropanol and 4.6
4 g of crystals were obtained. [α]. 2・+16.44@(C1
, 09° water), a part of this was reacted with 3,5-dinitrophenyl isocyanate to convert it into a urea derivative,
As a result of analysis by high performance liquid chromatography using an optically active column, the optical purity was 87.2%.

(3-2) (+)-1-(2-benzyloxyphenylpropylamine THF141) d and (S)- (-)-2-amino-3
-Methyl-1,1-diphenylbutanol 9.3 g
(0.0364 mol) at -78°C
borane dimethyl sulfide complex 2 under stirring.
．． After adding 90g, the temperature was raised to room temperature over about 3 hours,
Furthermore, 2.90 g of borane dimethyl sulfide complex was added and stirred for 15 minutes. Next, 7 g (0.026 mol) of 2-benzyloxypropionphenone-〇-methyloxime obtained in Reference Example 2-2 and THF 1
A mixture with 01d was added, and the mixture was stirred at room temperature for 20 hours and at 50°C for 1 hour.

Then, in the same manner as in Reference Example (3-1), 4.5 g of (+)-1-(2-benzyloxyphenyl)propylamine was obtained by adding 10% hydrochloric acid, vacuum concentration, alkali neutralization, chloroform extraction, and column chromatography purification. I got it. It was oily and had an optical purity of 49.6%.

'Hrv+r spectrum (δ,,., CDCIs)0
, 89 (311, t) , 1.58 (2H, S)
, 1.67-1.98 (2Lq) 4, 12 (H,
t), 5.08 (2H, S), 6.8~? -35 (4H
1m) 7,39(5H,S) Dissolve 5.17 g of the hydrochloride of this product in 170 d of water, add 3.23 g of N-acetyl-cy-leucine, IN NaO H2O. A solution consisting of 61d was added. When the precipitated crystals were collected by filtration, 3.40 g of (+)-1-(2
N-acetyl-L-leucine salt of -benzyloxyphenyl)propylamine ([α) o''+12.1.

(CO.5.water)) was obtained.

Next, this was added to an aqueous solution of caustic soda to form a free amine, and extracted with chloroform to obtain an oily, 1.95
g of (+)-1-(2-benzyloxyphenyl)propylamine was obtained. Optical purity was 97.0%.

[α) D''+14.86' (C1,0, water) (hydrochloride) (3-3) (-)-1-(2-benzyloxy-3-methylphenyl)ethylamine (S)-2-amino 15.83 g (0,062 mol) of -3-methyl-1,1-diphenylbutanol and 1.
A mixture of 260 d of 2-dichloroethane was cooled to -30°C, and 4.95 g of borane dimethyl sulfide complex was added thereto.
was added and the temperature was raised to 10°C over 2 hours, and then 4.95 g of porandimethyl sulfide complex was added and the temperature was raised to room temperature over 1 hour.

Next, 2-benzyloxy-3 obtained in Reference Example 2-3
-Methylacetophenone-0-methyloxime 11.9
Add a mixture of 3 g (0,0443 mol) and 15 ml of 1,2-dichloroethane, and heat at 50°C for 21 hours at room temperature.
After stirring for 1 hour, 1201d of 10% hydrochloric acid was added.

Precipitated (S)-(-)-2-amine-3-methyl-1
, 1-diphenylpukunol hydrochloride was removed by filtration, the filtrate was made alkaline with an aqueous caustic soda solution, and the growing layer was separated and concentrated under reduced pressure.

Next, in order to remove a small amount of ligands etc., it was purified by silica gel column chromatography using ethyl acetate as an eluent, and 5.2 g of (-)-1-(2-benzyloxy-3-methylphenyl) was obtained. Ethylamine was obtained. Optical purity was 79.8%.

[α] o”-4,8° (C1,4,/evening/-ru)
'Hnmr spectrum (δ, , 1IICDCI3)
1.36 (31, d), 1.62 (2H, S), 2
．． 35 (3+1.S) 4.47 (H, q), 4.85 (
2H, S), 7.0-7.6 (8H, m) (3-4)
(-)-1-(2-benzyloxy-3-methoxyphenyl)ethylamine In Reference Example (3-3), 2, benzyloxy-3- obtained in Reference Example 2-4 was used as the oxime ether compound.
Methoxyacetophenone-〇-methyloxime 8.56
Reference Example (3-3) except that g (0.03 mol) was used.
) to give 5.0 g of (-)-1-(2-benzyloxy-3-methoxyphenyl)ethylamine.
9 was obtained, and the optical purity was 73.6%.

[α]. ”-28,1° (C1,0, water) (hydrochloride)
The hydrochloride of this product was dissolved in 20 d of water, and N-acetyl-
3.36 g of leucine and IN aqueous solution of caustic soda 1
9. Added to a solution consisting of 1*1.

The precipitated crystals were collected by filtration, converted into free amines using an aqueous solution of caustic soda, and then extracted with methylene chloride to obtain 3.17 g of (-)-1-(2-benzyloxy-3-methoxyphenyl). ) Ethylamine was obtained.

The optical purity was 95.0%.

[α) D''-35,66° (CO, 99, water) (hydrochloride)' Hnmr spectrum [δ, , , CDC1
5) 1.29 (3) 1. d), 2.63 (2H, S),
3.88 (3H, S).

4.83 (IH, q), 5.04 (2H, S), 6.8
~7.17 (3H, m).

7.2-7.55 (5H, m) (3-5) (+)-1-(2-benzyloxy-5
-Methoxyphenyl)ethylamine In Reference Example (3-3), 2-benzyloxy-5- obtained in Reference Example 2-5 was used as the oxime ether compound.
Methoxyacetophenone-〇-methyloxime 7.42
Reference Example (3-3) except that g (0,026 mol) was used.
) and purified in the same manner as (+)-1-(2-benzyloxy-5-methoxyphenyl)ethylamine 3.7
6 g was obtained. Optical purity was 62.2%.

The optical rotation of the hydrochloride of this product is [α)n''+2.45° (CO, 94, water), and by recrystallizing from isopropanol, the optical rotation of the hydrochloride with optical purity of 95.2% is 2.68°.
g was obtained.

[α]. ``+3.41@(C1,0, water) (hydrochloride)'
Hnsr spectrum [δppm, CDCh]1.
39 (3B, d), 1.69 (2H, S), 3.77 (
3)1. S).

4.42 (2H, q), 5.04 (28, S), 6.6
~? -0(3H1m)+7.2~7.5(5H,+a) (3-6) (-)-1-(3-hensyloxyphenyl)ethylamine In reference example (3-3), as an oxime ether compound The reaction and purification were carried out in the same manner as in Reference Example (3-3) except that 6.64 g of 3-benzyloxyacetophenone-0-methyloxime obtained in Reference Example 2-6 was used.
)-1-(3-benzyloxyphenyl)ethylamine was obtained. Optical purity was 87.4%.

[α]. ”-2,56° (C1,05, water) (hydrochloride) (3-7) (-) and (+)-1-(2-benzyloxyphenyl)ethylamine Obtained in the same manner as in Reference Example 2-1. 56.26 g of 2-benzyloxyacetophenone-〇-methyloxime (
26.47 g of borane dimethyl sulfide complex (0.22 mol) and 250 m of THF at room temperature.
, 352 mol) was added thereto, stirred for 5 hours, and then heated overnight.

After adding 10% hydrochloric acid to the reaction mass to decompose the reducing agent, adding an aqueous solution of caustic soda to make it alkaline, extracting with methylene chloride, washing with water, drying, concentrating, and distilling.
48.6g of (±)-1-(2-benzyloxyphenyl)ethylamine bp 152-153°C/1.8+
++n+Hg was obtained.

Next, this was made into a hydrochloride with hydrochloric acid, and this hydrochloride was converted to 1.31
9 g (5 mmol) and 14 I of water! 0.761 g of (+)-mandelic acid (5
When 1-1 IN of water and 5 m of a caustic soda aqueous solution were added, crystals were precipitated. Add 5 ml of water and recrystallize to obtain crude (-)-1-(2-benzyloxyphenyl)
0.93 g of (+)-mandelate of ethylamine ((
α) l124+36.3° (CO, 97, water)) was obtained.

By recrystallizing this with water, 0.53 g ([α]
. ! '+32.04'' (G O, 82, water)) was obtained. This salt was decomposed with an aqueous solution of caustic soda and extracted with chloroform to yield (-)-1-(2-benzyloxyphenyl)ethylamine 0.31 g was obtained.

([α) off419.1@(C1,0, water) (hydrochloride)) When analyzed by high performance liquid chromatography using an optically active column, the optical purity was 99% or more.

The (+) mandelate of crude (-)-1-(2-benzyloxyphenyl)ethylamine was separated by filtration, and the crystals precipitated from the mother liquor were collected by filtration and dried to yield (+)-1-(2-benzyloxyphenyl mandel). 0.31g of acid salt ((α)D”+59.3
5" (CO.83.water)) was obtained. This was decomposed with an aqueous solution of caustic soda and then extracted with chloroform to obtain 0.18 g of (10)-1-(2-benzyloxyphenyl)ethylamine ((α) o”+19.
27@(C 1.1.

Water) (hydrochloride)) was obtained. Its optical purity is 98.2
%Met. mp154-156℃ (hydrochloride) Reference example 4
(Production example of optically active hydroxybenzylamine derivative) (+) obtained in Reference Example (3-1) in methanol 40d
- Add 2.64 g of hydrochloride of 1-(2-benzyloxyphenyl)ethylamine and 0.26 g of 5% pd-C,
When hydrogenated at room temperature and pressure, 2561d of hydrogen was absorbed. After filtering off the catalyst, the mixture was concentrated under reduced pressure to obtain 1.87 g of (+)-1-(2-hydroxyphenyl)ethylamine hydrochloride.

[α]. ”+21.36° (C 1.06, water), m
1.3 g of (+)-1-(2-hydroxyphenyl)ethylamine was obtained by neutralizing the p 135-136° diluted with aqueous ammonia and extracting with methylene chloride.

(ff) D”+12.24° (C 1.1, C
HCb)mp83-83.5℃' Hnar spectrum [619m, CDCIs-D
MF-dy) hydrochloride 1, 70 (31 (, mouth), 4.70 (IH, q), 6.
6-7.5 (4H+n+).

7, 4-8.7 (4H, broad) Reference example (4-
In 1), instead of (+)-1-(2-benzyloxyphenyl)ethylamine, (+)-1-(2-benzyloxyphenyl)propylamine hydrochloride 1 obtained in Reference Example (3-2) was used. Using .37 g, the procedure was carried out according to Reference Example (4-1) to obtain 0.95 g of (+)-1-(2-hydroxyphenyl)propylamine hydrochloride.

[α) o” +28.6° (C 1.2, water) m
0.72 g of free amine was obtained in the form of an oil by neutralizing the p 194 to 196° filter in the same manner as in Reference Example (4-1).

[α) o”+17.21° (C 1.32, CO
Cl)) InIlr spectrum [δppm, CDC
l3] 0.89 (3B, t), 3.96 (H, t)
, 1.75 (2H, m).

6.6-7.25 (4H, +s), 3.5-5.5 (
38, broad) In reference example (4-1) (+)-
(-)-1-(2-) obtained in Reference Example (3-3) instead of 1-(2-benzyloxyphenyl)ethylamine
Using 2.61 g of benzyloxy-3-methylphenyl)ethylamine hydrochloride, 1.38 g of (
+)-1-(2-hydroxy-3-methylphenyl)ethylamine was obtained in the form of crystals. Recrystallization from cyclohexane yielded 1.08 g. Optical purity was 98.8%.

[α]D″S+17.8′ (C1,1,CHCl3
)mp 115-116 °C' Hr+nr spectrum [δppm, CDCIsC
DCl5-D) hydrochloride 1.68 (3H, d), 4.80 (11 (, q),
2.29 (3H, s) 6.68-7.40 (311, s
), 7.8-9.0 (48, broad) Reference example (4-
In 1), (-)-1-(2-benzyloxy-3-methoxyphenyl)ethylamine obtained in Reference Example (3-4) was used instead of (+)-1-(2-benzyloxyphenyl)ethylamine. Using 3.21 g of hydrochloride, 1.81 g of (+)-1-(2-hydroxy-
Crystals of 3-methoxyphenyl)ethylamine were obtained. m
p95~97°C (a) a”+13.14@(C1
,04,ethyl acetate)'Hnmr spectrum [δppm
, CDCh) 1.46 (3H, d), 3.86 (3H
,s), 4.35 (IH,'q) 4.4-5.0 (3L
Broad) In Reference Example (4-1), Reference Example (3-5) was used instead of (+)-1-(2-benzyloxyphenyl)ethylamine.
) obtained (+)-1-(2-benzyloxy-5-
Using 2.57 g of hydrochloride of methoxyphenyl)ethylamine, reaction and neutralization were performed according to Reference Example (4-1) to obtain an oily substance (+)-1-(2-hydroxy-5
1.42 g of -methoxyphenyl)ethylamine was obtained.

[α) n”+21.70' (CO,96,CHC
l5) In Reference Example (4-1), instead of (+)-1-(2-benzyloxyphenyl)ethylamine hydrochloride, (-)-1-(3- Using 3.21 g of benzyloxyphenyl)ethylamine hydrochloride, a reaction was carried out according to Reference Example (4-1).

After removing the catalyst by filtration, 1.60 g of (-)-1-(3-
Hydroxyphenyl)ethylamine was obtained.

(α) o”-24,52@(CO,98,ethyl acetate)' Hna+r spectrum (δ1) I) II, CD
C13) 1.40 (3H, d), 3.0 to 3.4 (3H
, s), 4.09 (II, Q) 6.6 to 6.9 (3L+
w), 7.08-7.2 (1) 1) Example 1 Consisting of (+)-1-(2-hydroxyphenyl)ethylamine 0.1372 g (1 mmol) and deuterated chloroform 4d under nitrogen atmosphere To the solution was added 0.10 d (1 mmol) of borane dimethyl sulfide complex at O'C, and the mixture was stirred for 1 hour and then at room temperature for 0.5 hour.

Further, 0.10 d (1 mmol) of borane dimethyl sulfide complex was added to this, and the mixture was stirred at room temperature for 0.75 hr.
An optically active amine-boron compound was produced.

When the Bnmr spectrum of this product was measured, it was as follows.

[δppm, BF, ・OEt, standard] -37,
1, -20, 2, +1.3. +2.5. +21.0°+
26.1 Examples 2 to 4 In Example 1, (+)-1-(2-hydroxy-3-methoxyphenyl)ethylamine, (+)-1-(2-hydroxyphenyl)ethylamine was used instead of (+)-1-(2-hydroxyphenyl)ethylamine.
Using -1-(2-hydroxy-3-methylphenylulamine and (+)-1-(2-hydroxy-5-methoxyphenyl)ethylamine, optically active amine-boron compounds were prepared according to Example 1. Manufactured.

”The measurement results of Bnmr are shown in Table 1.

Example 5 0.9 mmol (0.12 mmol) of (+)-1-(2-hydroxyphenyl)ethylamine obtained in Reference Example (4-1)
A mixture of 4 g) and 2.5 d of THF was cooled to -78°C, 0.9 mmol (1,15 Inff1) of 0.78 M borane-THF solution was added thereto, and the temperature was raised to room temperature over 2 hours while stirring. did. In addition to this, 0.78M borane-
0.9 mmol of THF solution was added and stirred for 30 minutes.

Next, 2-benzyloxyacetophenone-0-methyloxime (anti/syn-88/12) was added to this at room temperature.
A solution consisting of 0.6 mmol (0,153 g) and THF2r11 was added, stirred at room temperature for 24 hours, and then heated at 45°
The mixture was stirred at C for 1.5 hours.

Next, add 4 tl of 10% hydrochloric acid to the reaction mass! The mixture was concentrated under reduced pressure, and diethyl ether and water were added thereto to separate the layers. The aqueous layer was made alkaline with aqueous caustic soda solution and then extracted with chloroform to yield 0.12 g of (-)-1-(2
-benzyloxyphenyl)ethylamine was obtained (
The yield was 88%), and the optical yield was 50%.

The remaining aqueous layer extracted with chloroform was acidified with hydrochloric acid, neutralized with ammonia, and extracted with chloroform to recover 0.10 g of (+)-1-(2-hydroxyphenyl)ethylamine as crystals. It was done.

The optical purity was 87.2%, the same as before use.

Examples 6 to 12, Comparative Example 1 Based on Example 5, various optically active benzylamines obtained in Reference Examples (4-1) to (46) and (-)-1
Acetophenone-〇-methyloxime (anti/syn-97/3) was asymmetrically reduced using -(4-hydroxyphenyl)ethylamine as an asymmetric ligand to obtain (+)-α-phenethylamine.

The results are shown in Table 3.

Table 3 *2: (+)-α-Phenethylamine Examples 13 to 23 In Example 5, various substrates shown in Table 4 were used instead of 2-benzyloxyacetophenone-0-methyloxime, and the results were based on Example 5. The reaction was carried out. Table 4 shows the results.
It was shown to.

Example 24 In Example 5, (-)-1-(3-hydroxyphenyl)ethylamine was used instead of (+)-1-(2-hydroxyphenyl)ethylamine, and 2-benzyloxyacetophenone-〇-methyloxime was prepared. The reaction was carried out in the same manner as in Example 5, using phenyl(p-tolylmethyl)ketone-0-methyloxime instead. The results are shown in Table 4.

Comparative Example 2 The reaction was carried out in the same manner as in Example 24, except that (-)-1-'(4-hydroxyphenyl)ethylamine was used instead of (-)-1-(3-hydroxyphenyl)ethylamine. . The results are shown in Table 4.

Example 25 Under a nitrogen atmosphere, 3.75 mmol of borane dimethyl sulfide was added to a solution consisting of 1.5 mmol (0,206 g) of (+)-1-(2-hydroxyphenyl)ethylamine and 4 d of tetrahydrofuran at -30''C. (0,-37
After adding 5m), the temperature was raised to room temperature over 2 hours.

A solution consisting of 1 mmol (0.12 g) of acetophenone and 1 d of tetrahydrofuran was added to this and stirred for 24 hours.

Next, 3d of 10% hydrochloric acid was added and stirred at 50°C for 1 hour, extracted with chloroform, washed with 10% hydrochloric acid, washed with water,
After drying, (-)-1-phenylethanol was obtained with a reaction rate of 100%.

This was converted into a urethane derivative, and the isomer ratio was analyzed by high performance liquid chromatography using an optically active column to determine the optical yield. The results are shown in Table 5.

Examples 26 to 28 The procedure of Example 25 was carried out using n-propylphenyl ketone, 1so-propylphenyl ketone, and methyl-n-hexyl ketone instead of acetophenone. The results are shown in Table 5.

Example 29 The procedure of Example 25 was repeated except that (-)-1-(3-hydroxyphenyl)ethylamine was used instead of (+)-1-(2-hydroxyphenyl)ethylamine. The results are shown in Table 5.

Comparative Example 3 The same procedure as in Example 25 was carried out except that (+)-α-phenylethylamine was used instead of (+)-1-(2-hydroxyphenyl)ethylamine. The results are shown in Table 5.

Examples 30-36 In Example 25, using 1-substituted-2-triazol-1-yl 4.4, dimethyl-1-penten-3-one having various substituents instead of acetophenone,
It was carried out according to Example 25. The results are shown in Table 6.

Table 5 The procedure was carried out according to Example 37 using (-)-1-(4-hydroxyphenyl)ethylamine and (+)-α-phenylethylamine instead of phenyl)ethylamine. The results are shown in Table 6.

Example 37 In Example 25, 1-(2
,4-dichlorophenyl)-2-)lyazol-1-yl 4,4-dimethyl-1-penten-3-one,
The procedure was carried out according to Example 25 using (-)-1-(3-hydroxyphenyl)ethylamine instead of (+)-1-(2-hydroxyphenyl)ethylamine. The results are shown in Table 6.

Comparative example 4.5

Claims (2)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and R^2 represents a lower alkyl group. .*
means an asymmetric carbon, and the OH group is substituted at the o-position or m-position of a substituent having an asymmetric carbon. ) An optically active amine-boron compound obtained from an optically active amine derivative and a boron hydride compound. (2) An asymmetric reducing agent containing the optically active amine-boron compound according to claim 1 as an active ingredient. (3) The optically active amine-boron compound according to claim 1 has the general formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R^3 is a hydrogen atom, an alkyl group, an aralkyl group, etc.) R^4, R^ representing a group or an alkyl-substituted silyl group
5 represents a lower alkyl group, an aryl group or an aralkyl group, and they are not the same. ) A mixture rich in the anti- or syn-isomer of oximes, or a mixture thereof, or the general formula (III) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (III) (In the formula, R^6, R^ 7 is a lower alkyl group, an aryl group, or the formula (VI) ▲ Numerical formula, chemical formula, table, etc. ▼ (VI) (In the formula, R^8 is a phenyl group that may be substituted with a halogen or haloalkyl group, 2-substituted-1-triazoleethylene group represented by (or a cycloalkyl group), which are not identical.
V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R^4 and R^5 have the same meanings as above, and * represents an asymmetric carbon.) Optically active amines or Optical activity represented by general formula (V) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (V) (In the formula, R^6 and R^7 have the same meanings as above, and * represents an asymmetric carbon.) A method for producing an optically active compound, the method comprising producing an alcohol.